Neurologic Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1,Andifih1: Aicardi–Goutières Syndrome and Beyond

Review Article 355

Neurologic Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1,andIFIH1: Aicardi–Goutières Syndrome and Beyond

John H. Livingston1 Yanick J. Crow2,3

1 Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Address for correspondence John H. Livingston, MBCHB, Department Trust, Leeds General Infirmary, Leeds, United Kingdom of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds 2 Laboratory of Neurogenetics and Neuroinflammation, Institut General Infirmary, F Floor Martin Wing, Leeds, West Yorkshire, LS1 3EX, Imagine, Paris Descartes–Sorbonne Paris Cité University, United Kingdom (e-mail: [email protected]). Paris, France 3 Manchester Centre for Genomic Medicine, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom

Neuropediatrics 2016;47:355–360.

Abstract The Aicardi–Goutières syndrome (AGS) was first described in 1984, and over the following years was defined by the clinical and radiological features of an early onset, severe, neurologic disorder with intracranial calcification, leukoencephalopathy, and cerebral atrophy, usually associated with a cerebrospinal fluid (CSF) pleocytosis and elevated CSF interferon α activity. It is now recognized that mutations in any of the following seven genes may result in the classical AGS phenotype: TREX1 (AGS1), RNASEH2A (AGS2), RNASEH2B (AGS3), RNASEH2C (AGS4), SAMHD1 (AGS5), ADAR1 (AGS6), and IFIH1 (AGS7). All of these genes encode proteins involved in nucleotide metabolism and/or sensing. Mutations in these genes result in the induction of type 1 interferon production and an upregulation of interferon stimulated genes. As more patients harboring mutations in these genes have been described, in particular facilitated by the advent of whole exome sequencing, a remarkably broad spectrum of associated neurologic phenotypes has been revealed, which we summarize here. We Keywords propose that the term AGS has continued clinical utility in the designation of a ► Aicardi–Goutières characteristic phenotype, which suggests relevant diagnostic investigations and can syndrome inform outcome predictions. However, we also suggest that the use of the term “type 1 ► type 1 interferonopathy” is appropriate for the wider spectrum of disease consequent upon interferonopathies dysfunction of these genes and proteins since it implies the possibility of a common ► interferon signature “anti-interferon” approach to therapy as such treatments become available. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Introduction cerebrospinal ﬂuid (CSF) pleocytosis.1 Despite the resemblance In 1984, Jean Aicardi and Francoise Goutières described eight to congenital infection, the occurrence of affected siblings and children with an early onset, progressive, and severe neurologic consanguinity in some families suggested a genetic basis to this disorder demonstrating imaging features of intracranial calciﬁ- phenotype. In 1988, elevation of CSF and serum interferon α was cation (ICC), leukoencephalopathy, cerebral atrophy, and a demonstrated in these patients.2 Further cases were

received © 2016 Georg Thieme Verlag KG DOI http://dx.doi.org/ June 10, 2016 Stuttgart · New York 10.1055/s-0036-1592307. accepted after revision ISSN 0174-304X. July 21, 2016 published online September 19, 2016 356 Aicardi–Goutières Syndrome and Beyond Livingston, Crow

subsequently reported, cutaneous features and autoimmune the use of whole exome sequencing, has revealed a remark- disease were noted, and the condition became known as ably broad spectrum of disease phenotypes associated with – Aicardi–Goutières syndrome (AGS).3 8 mutations in the AGS-related genes.15 In the past decade, the genetic basis of AGS has been The preceding observations raise important points of determined, and it is now recognized that mutations in any of nosology, with practical implications for both clinicians seven genes can be associated with this phenotype, namely, and families. We have recently suggested the use of the TREX1 (AGS1),9 RNASEH2A (AGS2), RNASEH2B (AGS3), RNA- term “type I interferonopathies” as a novel disease grouping, SEH2C (AGS4),10 SAMHD1 (AGS5),11 ADAR1 (AGS6),12 and encompassing all monogenic phenotypes associated with a IFIH1 (AGS7).13 Mutations in these genes account for around pathological upregulation of type I interferon signaling, 95% of patients with classical AGS. In most cases, inheritance including those due to mutations in AGS1–7.16 Such a pro- is autosomal recessive; however, specific heterozygous gain- posal has its justification in the recognition that therapies of-function mutations have been observed in TREX1 and directed toward reducing type I interferon production and/or ADAR1, and all AGS-related mutations in IFIH1 are dominant. blocking type I interferon-induced signaling might be rele- Although experience suggests that AGS “runs true” in most vant to any patient with mutations in these genes. At the families, marked intrafamilial variation in disease expression same time, as physicians, we recognize that diseases present is also well recognized. By way of illustration, Vogt et al as clinical scenarios, and phenotypic classification can inform described a family harboring homozygous RNASEH2C muta- prognosis. tions in which one child had a severe AGS phenotype, Summary papers relating to the genotype–phenotype whereas a sibling with the same mutations demonstrated correlation and pathogenesis of the type I interferonopathies chilblains and a very mild hemiparesis, with completely have been published recently.15,17 Here, then, we have preserved cognitive function and a virtually normal magnetic decided to describe the range of currently recognized stereo- resonance imaging (MRI).14 Furthermore, and of particular typed clinical scenarios that can present to the pediatric note here, extended genetic screening, in particular through neurologist due to mutations in the seven AGS-related genes

Table 1 Summary of major clinical features associated with mutations in TREX1, RNASEH2A/B/C, SAMHD1, ADAR1, and IFIH1

Genotype TREX1 RNASEH2 A/B/C SAMHD1 ADAR1 IFIH1 Neurologic Developmental delay •• • • • Regression •• • • • Epileptic seizures •• • • • Motor disorder (dystonia/spasticity) •• • • • Eye movement abnormalities •• • • • Spastic paraparesis ••• Large vessel disease (stenosis/moyamoya/aneurysms) •• Bilateral striatal necrosis • Neuroimaging Intracranial calciﬁcation •• • • • White matter abnormality •• • • • Cerebral atrophy •• • • • This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Other Recurrent (sterile) fevers •• • • • Autoimmune features •• • • • Glaucoma •• • • Neonatal thrombocytopenia/bone marrow suppression •• • • • Hypertrophic cardiomyopathy •• • Chronic lymphocytic leukemia • Premature dental loss • Aortic calciﬁcation • Joint contractures •••

Note: Aortic calciﬁcation occurs in the Singleton–Merten syndrome (SMS) caused by mutations in IFIH1. Patients with overlapping features between SMS and Aicardi–Goutières syndrome have recently been reported.31

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(►Table 1). In some cases, these phenotypes represent dis- Later Onset Aicardi–Goutières Syndrome tinct clinical entities, triggering different clinical trains of thought, differential diagnoses, investigative strategies, and Although effectively comprising the similar clinical and radio- prognostic considerations. At the same time, we also high- logical markers, we highlight here that mutations in AGS1–7 light the fact that an overlap of core features can be observed, can present beyond the first year of life with the abrupt/ encompassing the clinical signs of spasticity and dystonia, subacute onset of profound neurologic regression.5,6,22,23 As and the radiological features of ICC and white matter disease, an example, we have seen a male with a de novo heterozygous which can thus serve as vital clues to the true underlying mutation in IFH1 who showed completely normal develop- diagnosis. ment until the age of 15 months, at which time he could walk and had 6 to 10 words. After this point, he developed inter- Prenatal Onset Aicardi–Goutières Syndrome mittent posturing and rigidity of his legs, and then of the upper extremities. He also developed exaggerated startle. He subse- Mutations in any of the seven AGS genes may result in this quently experienced a relentless loss of motor and intellectual phenotype. However, TREX1 mutations are most commonly skills, and by the age of 24 months, he was unable to sit associated with a true neonatal presentation that is, with unsupported and had lost the ability to swallow. Between onset of disease in utero. This clinical scenario represents a 15 months and 4 years of age, he demonstrated a fluctuating remarkable clinical mimic of transplacentally acquired infec- pattern of poor sleep, with persistent whining and crying. tion (pseudo-TORCH)—associated with disturbed neurology Now, at the age of 13 years, he has no useful hand function, at birth including irritability, feeding difficulties, jitteriness, cannot sit independently, and has limited words, although his microcephaly, abnormal movements, and epileptic seizures— understanding is relatively preserved. Calcification of the basal as well as hematological disturbance such as major throm- ganglia and white matter were observed on cranial CT imaging bocytopenia with petechia and anemia, and liver dysfunction. at the age of 2 years, with abnormal high signal of the deep Although these systemic features can resolve after a few white matter seen onT2 weighted MRI. Similar cases have been weeks, such a presentation is invariably associated with described in the context of mutations in RNASEH2B and ADAR1. profound developmental effects and a markedly increased risk of death in infancy. Bilateral Striatal Necrosis fi Infantile Onset Aicardi–Goutières Syndrome Dystonia represents a signi cant component of the neurologic phenotype in classical AGS.17 Following the identification of Demonstrating essentially the same features as the neona- mutations in the ADAR1 gene as the cause of AGS6, it was tal form described previously, AGS most frequently has a recognized that some patients with otherwise typical AGS also clinically obvious onset after birth, with patients initially had imaging evidence of bilateral striatal necrosis (BSN).24 leaving hospital and then presenting in the first few months Furthermore, some patients were identified who had pre- of life. In this scenario, parents frequently report the sented with an acute or subacute onset of dystonia with relatively abrupt onset of irritability and crying, with the imaging features of BSN rather than classical AGS. A review children being apparently inconsolable and sometimes of patients with unexplained severe dystonia identified further experiencing recurrent episodes of sterile pyrexias. In cases with this phenotype; therefore, it is now recognized that some cases, it is clear that development has been complete- ADAR1 mutations are an important cause of BSN.25 Most ly normal prior to this point, and disease onset is associated patients are normal before the rapid onset of dystonia associ- with a loss of previously acquired skills. In others, the initial ated with MR features characteristic of BSN. Importantly, in level of development is difficult to gauge. Whatever the many cases, the onset of disease was preceded by an infectious case, neurologic abnormalities commonly seen include illness. The clinical course can be severe, with progressive evolving limb hypertonia with truncal hypotonia, dystonia, dystonia and early death in some patients. Of note, disease excessive startle, eye movement abnormalities, and epilep- onset can occur early or much later in life (we are aware of one This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. tic seizures. The encephalopathic stage typically lasts for child with disease onset in her sixth year). ICC is not invariable several months, during which time there is neurologic in this situation; therefore, we strongly recommend that regression and a slowing of head growth. This clinical ADAR1-related disease be considered in any child presenting scenario, the most frequent presentation of AGS, can be with BSN or otherwise unexplained subacute onset dystonia. associated with mutations in any of the AGS-related genes, RNASEH2B although mutations in represent the most fre- Hereditary Spastic Paraparesis quent genotype seen in this context. In both scenarios described previously, the major clue to Peripheral hypertonia is invariable in patients with classical AGS. the diagnosis usually comes from neuroimaging with a highly However, recent experience, informed particularly by the results characteristic pattern comprising diffusely abnormal white of whole exome sequencing, has shown that patients with matter often with swelling of temporal or frontal lobes, “idiopathic spastic paraparesis” can be identified due to muta- cerebral atrophy, particularly involving anterior temporal tions in ADAR1, IFIH1,andRNASEH2B.26 We emphasize here that – lobes, and ICC (►Fig. 1).18 20 This combination of features neuroimaging can be completely normal. Our experience to date is essentially pathognomonic.21 indicates that this phenotype can be slowly progressive over

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Fig. 1 Imaging features associated with mutations in Aicardi–Goutières syndrome (AGS) related genes. (A–C) Computed tomography (CT) and (H–J)T2 magnetic resonance (MR) images of the classical AGS phenotype demonstrating (A, B) spot calcification of basal ganglia, thalami, and deep white matter and (C) calcification of pons and cerebellum. (H, I) Abnormal white matter with swelling of anterior temporal and frontal lobes. Also note the characteristic pattern of atrophy involving the anterior temporal lobes. Calcification is apparent on the (J) T2 MR image as low signal spots within the deep white matter. (D) CT and (K) MR image of a patient with a milder phenotype associated with RNASEH2B mutations showing subtle spot calcification in the putamen and deep frontal cortex (D) and normal MR appearances (K). Large cerebral artery disease is particularly associated with SAMHD1 mutations. (E) CT showing a subarachnoid hemorrhage and a large aneurysm of the left carotid artery. (L) MR image from a different patient shows old ischemic damage in the left occipital region and extensive moyamoya type basal neovascularization. (F) CT and (M) MR image of a patient with ADAR1 mutation-associated bilateral striatal necrosis. The CTshows bilateral calcification in the putamen. The T2 MR image shows bilateral high signal and swelling in the caudate and putamen. (G, N) Widespread deep white matter and basal ganglia calcification is demonstrated in these CT images from a mildy symptomatic adult harboring a dominant ADAR1 mutation. Her son, carrying the same dominant mutation (p.G1007R), has a typical AGS phenotype.

many years, being apparently confined to the lower limbs, and in contrast to her younger sibling, this young woman was identi- the context of completely preserved intellect. The oldest known fied to have significant cerebral large vessel disease on magnetic patient demonstrating this clinical scenario is now aged 34 years resonance angiography following the diagnosis of AGS in her and clinically has an isolated lower limb spasticity. sister.

SAMHD1-Related Cerebrovascular Disease Further Clues to the Diagnosis: Nonneurologic Features Although biallelic mutations in SAMHD1 can be associated with classical AGS, we have observed a marked variability in the Skin lesions, most frequently referred to as chilblains, are an clinical features associated with this genotype, which we discuss important feature of mutations in AGS1–7.7,8,17,28 They are This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. separately here. We emphasize that SAMHD1-related disease exacerbated by cold temperature and are thus more com- can be associated with a degree of developmental delay typical of monly seen in the winter months. Glaucoma is also a recur- classical AGS or with completely preserved normal intellect. Our rent feature, which can present in the neonate or later17,29; experience suggests that extraneurologic involvement (see therefore, currently we recommend screening at least annu- later), particularly skin disease and glaucoma, is frequently ally. Features of autoimmunity, most commonly thyroiditis presently in the context of this genotype. A particular feature and less frequently lupus-like disease, can also occur. of SAMHD1-related disease is the risk of intracerebral large vessel involvement, including moyamoya, aneurysms, stenosis of – 27 Is Aicardi Goutières Syndrome a Progressive single vessels with infarcts, and intracerebral hemorrhage. By Disorder? way of illustration, we know of a child with clinical and radiological features of typical AGS whose older sister, harboring Although initially considered a neurodegenerative, progres- the same homozygous mutation in SAMHD1,iscompletely sive disease, as more patients have been studied longitudi- intellectually normal with an unremarkable medical history nally, this point has come into question. In our opinion, the except for recurrent winter chilblains. Remarkably, and in most classical clinical course is of a period of several months

Neuropediatrics Vol. 47 No. 6/2016 Aicardi–Goutières Syndrome and Beyond Livingston, Crow 359 of neurologic regression in infancy associated with progres- with specific phenotypic features than others? What genetic sive radiological changes. For most patients, the disease then or environmental factors determine the sometimes marked stabilizes, leaving the child with profound disabilities. Death intrafamilial and between-gene variability of disease expres- in childhood occurs in a proportion of patients; however, for sion and penetrance? most, the course is one of survival without further evident We hold that the term AGS has clinical utility as the deterioration. A recent review of 374 patients with mutations designation of a characteristic phenotype, which suggests in the seven AGS-related genes identified 67 (19.3%) patients relevant diagnostic investigations and can inform predictions who had died (half before the age of 5 years), 68 (19%) who of outcome. However, the diverse phenotypic spectrum had lived beyond 15 years of age, and 8 beyond the age of associated with mutations in the AGS-related genes also 30 years.17 Of the almost 300 patients, where data were indicates that the possibility of a genetic interferonopathy available, 210 (74%) had profound neurodisability (with no needs to be considered in the workup relating to several useful motor, speech, or intellectual function). Considering clinically distinct neurologic scenarios. The presence of tell- the fact that skin involvement can be recurrent and evidence tale clinical features such as ICC and chilblains is diagnosti- of upregulated interferon signaling can be lifelong, “why” the cally suggestive. However, the absence of such features does disease is not more “obviously progressive” is unknown. not exclude the diagnosis. The more widespread availability Thus, the possibility of very slow progression and/or disease of whole exome/genome sequencing is likely to identify flares remains. Clear progression has been observed in the further patients in whom the identification of mutations in context of the single dominant G1007R mutation in ADAR1 one of the AGS-related genes comes as a clinical surprise. and in certain patients with spastic paraparesis.

The Concept of the Type 1 Interferonopathies Acknowledgments Y.J.C acknowledges funding from the European Research All of the seven genes that cause AGS are involved in nucleo- Council (GA 309449: Fellowship to Y.J.C) and a state subsidy tide metabolism and/or sensing. TREX1 and RNASEH2A/B/C managed by the National Research Agency (France) under are nucleases targeting deoxyribonucleic acid (DNA) and the “Investments for the Future” (ANR-10-IAHU-01). DNA–ribonucleic acid (RNA) hybrids, respectively. SAMHD1 has a role in regulating cytosolic deoxynucleotides, ADAR1 is a double-stranded RNA (dsRNA) editing enzyme, and IFIH1 is a cytosolic receptor for dsRNA. Mutations in any of these genes References can result in an induction of type 1 interferon production and 1 Aicardi J, Goutières F. A progressive familial encephalopathy in fi an upregulation of interferon-stimulated genes. At a cellular infancy with calci cations of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 1984;15(1):49–54 level, this is analogous to the type 1 interferon response 2 Lebon P, Badoual J, Ponsot G, Goutières F, Hémeury-Cukier F, following exposure to viral DNA or RNA, thus perhaps Aicardi J. Intrathecal synthesis of interferon-alpha in infants explaining why the clinical features of AGS may resemble with progressive familial encephalopathy. J Neurol Sci 1988; those of a viral infection. However, in contrast to exogenous 84(2–3):201–208 viral infection, AGS is considered to represent an abnormal 3 Lanzi G, Fazzi E, D’Arrigo S. Aicardi-Goutières syndrome: a description response to endogenous or self-derived nucleic acids.15,16 of 21 new cases and a comparison with the literature. Eur J Paediatr Neurol 2002;6(Suppl A):A9–A22, discussion A23–A25, A77–A86 The detection of elevated levels of interferon α in the CSF 4 Goutières F. Aicardi-Goutières syndrome. Brain Dev 2005;27(3): and blood of patients with AGS was recognized soon after the 201–206 2 disorder was described. More recently, evidence for abnor- 5 Crow YJ, Livingston JH. Aicardi-Goutières syndrome: an important mal interferon activity in AGS has been demonstrated by Mendelian mimic of congenital infection. Dev Med Child Neurol identifying an “interferon signature” in peripheral blood. The 2008;50(6):410–416 6 Rice G, Patrick T, Parmar R, et al. Clinical and molecular phenotype of interferon signature measures the expression of interferon Aicardi-Goutières syndrome. Am J Hum Genet 2007;81(4):713–725 stimulated genes and has been identified in almost 100% of This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 7 Tolmie JL, Shillito P, Hughes-Benzie R, Stephenson JBP. The Aicardi- patients with mutations in TREX1, RNASEH2A, RNASEH2C, Goutières syndrome (familial, early onset encephalopathy with SAMHD1, ADAR1,andIFIH1.30 Of note, depending on the calcifications of the basal ganglia and chronic cerebrospinal fluid age at testing, up to 30% of patients with mutations in lymphocytosis). J Med Genet 1995;32:881–884 RNASEH2B might not show an interferon signature. 8 Dale RC, Tang SP, Heckmatt JZ, Tatnall FM. Familial systemic lupus erythematosus and congenital infection-like syndrome. Neuro- pediatrics 2000;31(3):155–158 Conclusion 9 Crow YJ, Hayward BE, Parmar R, et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Gou- The unraveling of the genetic basis and pathogenesis of AGS tières syndrome at the AGS1 locus. Nat Genet 2006;38(8):917–920 has confirmed the original hypothesis of Aicardi, Goutières, 10 Crow YJ, Leitch A, Hayward BE, et al. Mutations in genes encoding and Lebon concerning the pathogenic similarity of the disease ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection. Nat Genet 2006;38(8): to congenital infection and the central role of interferon. At 910–916 the same time, the phenotypic diversity described previously 11 Rice GI, Bond J, Asipu A, et al. Mutations involved in Aicardi- raises several important and currently unanswered questions Goutières syndrome implicate SAMHD1 as regulator of the innate including why are some genes more frequently associated immune response. Nat Genet 2009;41(7):829–832

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